1. CRYPTOGENIC STROKE
Epidemiology, Pathophysiology, Diagnosis and Follow-Up
Reveal LINQTM
Insertable Cardiac Monitoring System
Reveal LINQTM
Insertable Cardiac Monitoring System

2. Why Talk About Cryptogenic Stroke?
Ischemic Stroke
678,000 ischemic strokes every year in the US1
Leading cause of disability in the US and worldwide
~200,000 cryptogenic strokes yearly1
Most cryptogenic stroke patients receive anti-platelet for secondary prevention2
Long-term monitoring reveals AF in ~30% of cryptogenic stroke patients3-9
These patients benefit from anticoagulant therapy
Large Vessel
Small Vessel
Other
Cryptogenic Stroke
Cardioembolic
20%
30%
30%
Cryptogenic Stroke
15%
NOTES
This presentation focuses on cryptogenic stroke—which can be defined simply a stroke for which a definite etiology cannot be determined1
Each year in the US, there are about 680,000 ischemic strokes.2 According to the US Census Bureau, stroke is the leading cause of serious long-term disability in the United States.2 At 6 months following a stroke, 50% of patients have remaining hemiparesis, 30% are unable to walk without assistance, 46% have cognitive deficits, 35% have depressive symptoms, 19% have aphasia, 26% are dependent on others for activities of daily living, and 26% were institutionalized in a nursing home
Of these, about 30% are cryptogenic.3-8 Most of these patients will receive antiplatelets for secondary prevention;9 however, long-term monitoring studies have revealed that up to 30% of these patients have AF10
While the detection of AF in a secondary stroke prevention patient does not prove that their stroke was caused by AF, it generally warrants a change in secondary prevention regimen from an oral antiplatelet agent to an oral anticoagulant. In fact, in clinical studies of AF detection modalities in cryptogenic stroke patients, all—or nearly all patients—in whom AF was detected were started on anticoagulant therapy.
REFERENCES
Adams HP, Bendixen BH, Kapelle LJ. Classification of subtype of acute ischemic stroke: Definitions for use in a multicenter clinical trial. Stroke. 1993;24:35-41.
Mozzafarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update. Circulation. 2015;131:e29-e322.
Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol. 1989;25(4):
Petty GW, Brown RD, Jr., Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke. 1999;30:
Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke. 2001;32:
Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke. 2003;34:
Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke. 2004;35:
Lee BI, Nam HS, Heo JH, Kim DI. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. Cerebrovasc Dis. 2001;12:
Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370: 5%
1 Mozzafarian D, et al. Circulation. 2015;131:e29-e322.
6 Schulz UG, et al. Stroke. 2003;34:
2 Kernan WN, et al. Stroke. 2014;45:
7 Schneider AT, et al. Stroke. 2004;35:
3 Sacco RL, et al. Ann Neurol. 1989;25:
8 Lee BI, et al. Cerebrovasc Dis. 2001;12:
4 Petty GW, et al. Stroke. 1999;30: Kolominsky-Rabas PL, et al. Stroke. 2001;32:
9 Sanna T, et al. N Engl J Med. 2014;370:

3. Stroke as a Healthcare Issue
~800,000
87%
5th
LEADING CAUSE
new or recurrent strokes yearly
ischemic; 13% hemorrhagic
leading cause of death
of serious long-term disability in the US
NOTES
Each year, approximately 800,000 Americans experience a new or recurrent stroke <Mozzafarian 2015, p e180A>
Ischemic stroke accounts for 87% of strokes overall, with the remaining 13% classified as hemorrhagic in origin Mozzafarian 2015, p e180A>
Strokes have severe consequences; in the United States, stroke is the fourth-leading cause of death, causing approximately 1 of every 20 deaths in 2011 <Mozzafarian 2015, p e181A>
According to the US Census Bureau, stroke is the leading cause of serious long-term disability in the United States
REFERENCES
Mozzafarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update. Circulation. 2015;131:e29-e322.
Source: Mozzafarian D, et al. Circulation. 2015;131:e29-e322.

4. DISABILITY ASSOCIATED WITH STROKE
Percent
NOTES
According to the US Census Bureau, stroke is the leading cause of serious long-term disability in the United States. <AHA 2013, p e158A>
At 6 months following a stroke, 50% of patients have remaining hemiparesis, 30% are unable to walk without assistance, 46% have cognitive deficits, 35% have depressive symptoms, 19% have aphasia, 26% are dependent on others for activities of daily living, and 26% are institutionalized in a nursing home.
REFERENCE
Go AS, Mozaffarian D, Roger VL et al. Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation. 2013;127:e6-e245.
Source: Go AS, et al. Circulation. 2013;127:e6-e245.

5. Importance of Secondary Ischemic Stroke Prevention
Recurrent Stroke Rate among Patients Discharged with a Primary Diagnosis of Stroke, South Carolina, 2002 (N = 10,399) % %
NOTES
Although preventing recurrent stroke is imperative, it is clear that having a first stroke dramatically increases the risk for subsequent stroke.
In this study, patients with a primary diagnosis of stroke discharged from the year 2002 were identified from the state hospital discharge database. Kaplan-Meier estimates of recurrent stroke, MI, vascular death, all-cause death, and composite events were calculated at 1 month, 6 months, 1 year, 2 years, 3 years, and 4 years.
The Kaplan-Meier estimate of cumulative risk at 1 month, 6 months, 1 year, 2 years, 3 years, and 4 years for recurrent stroke was 1.8%, 5.0%, 8.0%, 12.1%, 15.2%, and 18.1%
REFERENCE
Feng W, Hendry RM, Adams RJ. Risk of recurrent stroke, myocardial infarction, or death in hospitalized stroke patients. Neurology. 2010;74:588–593.
Source: Feng W, et al. Neurology. 2010;74:588–593.

6. Definitions of Cryptogenic Stroke
Classification Scheme
Required Work-up
TOAST1
Not specified
Causative Classification of Stroke (CCS)2
Brain CT/MR, 12-lead ECG, precordial echocardiogram, extra/intravascular imaging
Embolic strokes of undetermined source3
Brain CT/MR, 12-lead ECG, precordial echocardiogram, extra/intravascular imaging, cardiac monitoring for ≥ 24 hours
ASCO(D) phenotyping4
Does not include a cryptogenic stroke category %
NOTES
The number of patients placed into the cryptogenic stroke category depends completely on the rigor of the diagnostic workup.
The TOAST criteria do not specify a specific workup that is required prior to classifying patients with cryptogenic stroke. Instead, this category includes any stroke for which the cause cannot be determined with any degree of confidence.1 <Adams 1993, p 37B>
The Causative Classification of Stroke, or CCS, scheme, requires a number of tests be conducted with no conclusive result be conducted before classifying a stroke as cryptogenic. <CCS 2015, p 5>
An “embolic stroke of undetermined source” is defined as one with unknown causes after a required workup that includes cardiac monitoring for 24 hours or more.4 <Hart 2014, p 432A>
Finally, unlike other classification schemes, ASCO(D) phenotyping does not include a cryptogenic stroke category. Instead, it evaluates underlying diseases but acknowledges that no direct causal link can be made between these underlying diseases and the stroke.4 <Amarenco 2013, p 5A>
REFERENCES
Adams HP, Bendixen BH, Kapelle LJ. Classification of subtype of acute ischemic stroke: Definitions for use in a multicenter clinical trial. Stroke. 1993;24:35-41.
Causative Classification System for Ischemic Stroke (CCS). Available at: Accessed April 15, 2015.
Hart RG, Diener H-C, Easton JD et al. Embolic strokes of undetermined source: The case for a new clinical construct. Lancet Neurol. 2014;13:
Amarenco P, Bogousslavsky J, Caplan LR et al. The ASCOD phenotyping of ischemic stroke (updated ASCO phenotyping). Cerebrovasc Dis. 2013;36:1-5.
1 Adams HP, et al. Stroke. 1993;24:35-41.
2 Causative Classification System for Ischemic Stroke (CCS). Available at: Accessed April 15, 2015.
3 Hart RG, et al. Lancet Neurol. 2014;13:
4 Amarenco P, et al. Cerebrovasc Dis. 2013;36:1-5.

7. Cryptogenic Stroke is a Diagnosis of Exclusion
Atherosclerotic
Small arterial occlusion
Cardioembolic
Other causes
Cryptogenic
Arteroembolic*
Aortoembolic
Branch occlusive disease †
Paroxysmal atrial fibrillation
Paradoxical embolism
Cancer-related coagulopathy
Small arterial occlusion
Cardioembolic
Atherosclerotic*
Other causes
Cryptogenic %
NOTES
Cryptogenic stroke is, necessarily, a diagnosis of exclusion.
Atherosclerotic stroke can be classified into 4 categories based on extensive investigation in the poststroke setting. Small arterial occlusion, cardioembolic stroke and stroke due to other, infrequent etiologies can also be discerned as discrete categories. <Bang 2014, p 1191A>
Cryptogenic stroke—stroke that has no known cause after extensive evaluation—represents what is left over after all known causes of stroke have been excluded.
REFERENCE
Bang OY, Ovbiagele B, Kim JS. Evaluation of cryptogenic stroke with advanced diagnostic techniques. Stroke. 2014;45:
Source: Bang OY, et al. Stroke. 2014;45:

8. Risk for Stroke in Patients With AF
5-FOLD 2X
67%
increase in ischemic stroke risk for AF patients.1
more likely for AF-related ischemic stroke to be fatal as non-AF stroke.2
decrease in AF patient stroke risk with oral anticoagulants.3
NOTES
Data suggest that AF is associated with a 5-fold increased risk for ischemic stroke.1 Further, ischemic stroke in these patients is more likely to be associated with severe consequences; in fact, stroke is nearly twice as likely to be fatal in these patients vs non-AF patients.2
REFERENCES
Wolf PA et al. Arch Intern Med. 1987;147:
Lin HJ et al. Stroke. 1996; 27:
Stroke Prevention in Atrial Fibrillation Study. Circulation. 1991;84:
1 Wolf PA, et al. Arch Intern Med. 1987;147:
2 Lin HJ, et al. Stroke. 1996; 27:
3 Stroke Prevention in Atrial Fibrillation Study. Circulation. 1991;84:

9. Conventional Monitoring STRATEGIES
Holter Monitor
Event Recorder
Mobile Cardiac Telemetry
24-48 hours of monitoring
Up to 30 days of monitoring
External loop recorder
Event-triggered loop recorder
Saves all cardiac rhythm data
Saves events only
Saves all cardiac rhythm data
62% patient compliance1
53-90% patient compliance*2-5
NOTES
A number of conventional, external monitoring strategies are available. Holter monitors feasibly provide between 24 and 48 hours of monitoring, and save all cardiac rhythm data. Event recorders can provide up to 30 days of monitoring, but save events only. Mobile cardiac telemetry, likewise, provides up to 30 days of monitoring. All of these technologies, while highly sensitive and specific, have the disadvantage that patients may remove the monitors, limiting the practical duration that they can be used.
REFERENCES
Vasamreddy CR et al. J Cardiovasc Electrophysiol. 2006;17:
Gladstone DJ et al. N Engl J Med. 2014;370:
Rosenberg MA et al. Pacing Clin Electrophysiol. 2013;36:
Kamel H et al. Stroke. 2013;44:
Shinbane JS et al. Heart Rhythm Society th Annual Scientific Sessions, Volume 10, Issue 5S, 2013.
* Dependent on type of MCT.
1 Vasamreddy CR, et al. J Cardiovasc Electrophysiol. 2006;17: ; 2 Gladstone DJ, et al. N Engl J Med. 2014;370: ; 3 Rosenberg MA, et al. Pacing Clin Electrophysiol.
2013;36: ; 4 Kamel H, et al. Stroke. 2013;44: Shinbane JS, et al. Heart Rhythm Society th Annual Scientific Sessions, Volume 10, Issue 5S, 2013.

10. Studies of Outpatient Monitoring in Cryptogenic Stroke Patients
Study (Year) N
AF Definition
Monitoring Duration
AF Yield
Tayal (2006) 56
Any duration
MCOT 21 Days
Overall 23%
AF < 30 sec 18%
AF > 30 sec 5%
Gaillard (2010) 98
32 seconds
TTM 30 days 9%
Bhatt (2011) 62
30 seconds
MCOT 28 days
24%
AF > 5 min 9%
Flint (2012)
236
5 seconds
MCOT 30 days
Overall 11%
AF < 30 sec 4%
AF > 30 sec 7%
Kamel (2013) 20
MCOT 21 days 0%
Miller (2013)
156
Overall 17%
AF < 30 sec 12%
AF > 30 sec 4%
Gladstone (2014)
572
Event Monitor 30 days vs 24 Holter
16.1% in event monitor vs. 3.2% Holter
NOTES
Mobile cardiac outpatient telemetry (MCT) was designed to look for arrhythmias in patients outside the hospital setting. Several studies have evaluated the ability to detect AF after cryptogenic stroke using short-term monitoring.1
The incidence of new or silent AF discovered by outpatient monitoring ranges from 0% to 24% over a variable length of follow-up.1 <Glotzer 2014, p 2A>
The definition of “an episode of AF” in some of these studies was as short as 5 to 30 seconds in duration—at present, it is not clear if these extremely short AF episodes have any clinical significance.1 <Glotzer 2014, p 2A>
In addition, several of these studies found that a significant percentage of patients did not complete the prescribed monitoring course. For example, in EMBRACE—the largest and most rigorously conducted study of MCOT—only 61.7% of patients in whom AF was not detected completed the 4 weeks of the study.2 <Gladstone 2014, p 2471A>
REFERENCES
Glotzer TV, Ziegler PD. Cryptogenic stroke: Is silent atrial fibrillation the culprit? Heart Rhythm. 2015;12:
Gladstone DJ, Sharma M, Spence JD, Committee ES, Investigators. Cryptogenic stroke and atrial fibrillation. N Engl J Med. 2014;371:
Source: Glotzer TV, et al. Heart Rhythm. 2015;12:

11. Studies of Insertable Cardiac Monitors (ICMs)
Multiple studies have assessed the ability of ICMs to detect AF in patients with cryptogenic stroke
Cotter study
Ritter study
Etgen study
Rojo-Martinez study
SURPRISE
CRYSTAL AF
20%
30%
30%
Cryptogenic Stroke
15%
NOTES
Multiple studies have evaluated the ability of ICMs to detect AF in cryptogenic stroke
This section will briefly review some of the smaller studies of ICMs in this patient population, and then focus on CRYSTAL AF, the largest and most rigorously conducted of these studies.
REFERENCES
Glotzer TV, Ziegler PD. Cryptogenic stroke: Is silent atrial fibrillation the culprit? Heart Rhythm. 2015;12:
Source: Glotzer TV, et al. Heart Rhythm. 2015;12:

12. 20% 30% 15% CRYSTAL AF: Study Design and End Points
Randomized, controlled clinical trial with 441 patients
Compared continuous, long-term monitoring with Reveal™ ICM vs. conventional follow-up
Assessment at scheduled and unscheduled visits
ECG monitoring performed at the discretion of the site investigator
20%
30%
Cryptogenic Stroke
End Point
Primary
Time to first detection of AF at 6 months of follow-up
Secondary
Time to first detection of AF at 12 months
Recurrent stroke or TIA
Change in use of oral anticoagulant drugs
15%
NOTES
CRYSTAL AF was a randomized, controlled clinical trial that enrolled 441 patients, who were randomly allocated to continuous long-term monitoring with the Reveal ICM or to conventional follow-up, which included assessment at scheduled and unscheduled visits, with ECG monitoring performed at the discretion of the site investigator. Sanna 2014, p 2479B>
The primary end point of the study was time to first detection of AF at 6 months. <Sanna 2014, p 2479B>
Secondary end points included time to first detection of AF at 12 months, recurrent stroke or TIA, and the change in use of anticoagulant drugs.
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Source: Sanna T, et al. N Engl J Med. 2014;370:

13. 447 patients were enrolled 441 underwent randomization
CRYSTAL AF:
Study Population
447 patients were enrolled
6 were excluded
4 did not meet eligibility criteria
2 withdrew consent
441 underwent randomization
221 were assigned to ICM
208 had ICM inserted
13 did not have ICM inserted
220 were assigned to control
220 received standard of care
12 crossed over to control
12 exited the study
3 died
1 was lost to follow-up
5 withdrew
3 were withdrawn by investigator
6 crossed over to ICM
13 exited the study
2 died
1 was lost to follow-up
7 withdrew
3 were withdrawn by investigator
NOTES
At total of 447 patients were enrolled in the trial.
Of these, 441 underwent randomization.
A total of 221 were assigned to the ICM, of whom 13 did not have an ICM inserted. In total, 221 patients were included in the final analysis. <Sanna 2014, p 2481D>
220 patients were assigned to the control group, all of whom [arrow appears] were included in the final analysis.
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
221 were included in intention-to-treat analysis
220 were included in intention-to-treat analysis
Source: Sanna T, et al. N Engl J Med. 2014;370:

14. CRYSTAL AF:
PATIENTS
Age ≥ 40 years
Screening for thrombophilic states (in patients < 55 years of age)
Diagnosis of stroke or TIA occurring within previous 90 days
Magnetic resonance angiography, computerized tomography angiography, or catheter angiography of head and neck
Stroke was classified as cryptogenic after extensive testing:
Ultrasonography of cervical arteries or transcranial Doppler ultrasonography of intracranial arteries allowed in place of MRA or CTA for patients aged ≥ 55 years
12-lead ECG
≥ 24 hours of ECG monitoring
TEE
NOTES
Patients were required to be 40 years of age or older, and have a diagnosis of stroke or transient ischemic attack occurring within the previous 90 days. <Sanna 2014, p 2480A, B>
Stroke was classified as cryptogenic after extensive testing, including 12-lead ECG, 24 hours or more of ECG monitoring, TEE, screening for thrombophilic states in patients aged less than 55 years, and magnetic resonance angiography, computerized tomography angiography, or catheter angiography of the head and neck. Among patients aged 55 or older, ultrasonography of the cervical arteries or transcranial Doppler ultrasonography of the intracranial arteries was allows in place of MRA or CTA.
The key point is that patients were only categorized as have cryptogenic stroke after very extensive diagnostic testing. In actual fact, such extensive diagnostic testing is not the norm in everyday clinical practice—in such settings, the percentage of patients classified with cryptogenic stroke would likely be higher.
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Patients were only categorized with cryptogenic stroke after extensive diagnostic testing.
Source: Sanna T, et al. N Engl J Med. 2014;370:

15. Selected Baseline Patient Characteristics
CRYSTAL AF:
Selected Baseline Patient Characteristics
Characteristic
ICM
(n = 221)
Control
(n = 220) P
Age (years)
61.6 ± 11.4
61.4 ± 11.3
0.84
Male
64.3%
62.7%
0.77
White
87.8%
86.8%
0.60
Patent foramen ovale
23.5%
20.9%
0.57
Index event
0.87
Stroke
90.5%
91.4%
TIA
9.5%
8.6%
NOTES
At baseline, patients were, on average about 61 to 62 years of age. Most patients were male and white. About one-quarter of patients had a patent foramen ovale.
The index event was stroke in approximately 90% of patients, and TIA in approximately 10% of patients. <Sanna 2014, p 2482/Table 1>
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Source: Sanna T, et al. N Engl J Med. 2014;370:

16. CRYSTAL AF: AF DETECTION RATES NOTES
As shown here the incremental difference in the percentage of patients in whom AF was detected increased over time, from 6.4-fold at 6 months to nearly 9-fold at 36 months.
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Source: Sanna T, et al. N Engl J Med. 2014;370:

17. 97% of patients in whom AF was detected received oral anticoagulants
CRYSTAL AF:
Key Secondary End Point 12
months
97% of patients in whom AF was detected received oral anticoagulants
NOTES
The detection of AF had important therapeutic implications: At 12 months, 97% of patients in whom atrial fibrillation had been detected were receiving oral anticoagulants. <Sanna 2014, p 2482A>
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Source: Sanna T, et al. N Engl J Med. 2014;370:

18. 84 Days 53 Days in control group CRYSTAL AF:
Median Time to Detection of AF 84
Days
in the ICM group
(range 18 to 265 days) 53
Days in control group
(range 17 to 212 days)
NOTES
The detection of AF had important therapeutic implications: At 12 months, 97% of patients in whom atrial fibrillation had been detected were receiving oral anticoagulants. <Sanna 2014, p 2482A>
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Source: Sanna T, et al. N Engl J Med. 2014;370:

19. 20% CRYSTAL AF: Safety 2.4% removed due to infection or pocket erosion
Most common adverse events:
Infection (1.4%)
Pain (1.4%)
Irritation or inflammation (1.9%)
Device remained inserted in 98.1% of patients at 6 months and 96.6% at 12 months
20%
NOTES
Few safety concerns were identified in the CRYSTAL AF study. <Sanna 2014, p 2483A>
Of the 208 ICMs inserted, 5—or 2.4%—were removed due to infection at the insertion site or pocket erosion.
The most common adverse events associated with the ICM were infection (1.4%), pain (1.4%), and irritation or inflammation (1.4%).
The ICM remained inserted in 98.1% of patients at 6 months and in 96.6% at 12 months.
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Note: Reveal™ XT used in this study.
Source: Sanna T, et al. N Engl J Med. 2014;370:

20. Different Studies, Different Results
EMBRACE vs. CRYSTAL AF:
Different Studies, Different Results
CRYSTAL AF1
EMBRACE2
Inclusion Criteria
Age ≥ 40 years
Ischemic stroke or TIA within previous 90 days
Stroke classified as cryptogenic after extensive work-up
Age ≥ 55 years
Ischemic stroke or TIA within previous 6 months
Stroke classified as cryptogenic after standard work-up
Primary end point
Time to first detection of AF at 6 months follow-up
Detection of ≥ 1 episode of ECG-documented AF within 90 days
Definition of AF episode
AF lasting > 30 seconds*
AF lasting > 30 seconds
NOTES
CRYSTAL AF and EMBRACE—which evaluated the yield of a 30-day event-triggered recorder in patients with AF—are the 2 largest studies of monitoring for AF in the post-cryptogenic stroke setting.1,2
While both studies provide valuable information in this setting, they are distinguished not only by the monitoring technologies used, but also by their design.
CRYSTAL AF enrolled a younger patient population; these patients received an extensive workup prior to their strokes being classified as cryptogenic. In contrast, EMBRACE enrolled older patients who were classified with stroke after a standard workup.
It is important to note that, while the minimum duration of AF was 30 seconds in both studies, the device used in CRYSTAL AF required a minimum of 2 minutes of AF in order to qualify as an end point event.
REFERENCES
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014;370:
* For ICM group, episodes must have been > 2 minutes to be detected.
1 Sanna T, et al. N Engl J Med. 2014;370:
2 Gladstone DJ, et al. N Engl J Med. 2014;370:

21. Summary: Times to Detection of AF in
Clinical Studies of ICMs
Days from Insertion
NOTES
Average times to detection ranged from 48 days in the Cotter study (≥2 min AF) to 161 days in the Etgen study (≥6 min AF).1-6
REFERENCES
Cotter PE, Martin PJ, Ring L, Warburton EA, Belham M, Pugh PJ. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology. 2013;80:
Etgen T, Hochreiter M, Mundel M, Freudenberger T. Insertable cardiac event recorder in detection of atrial fibrillation after cryptogenic stroke: an audit report. Stroke. 2013;44:
Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke. 2013;44:
Rojo-Martinez E, Sandin-Fuentes M, Calleja-Sanz AI, et al. [High performance of an implantable Holter monitor in the detection of concealed paroxysmal atrial fibrillation in patients with cryptogenic stroke and a suspected embolic mechanism]. Rev Neurol. 2013;57:
Christensen LM, Krieger DW, Hojberg S, et al. Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE study. Eur J Neurol. 2014;21:
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370: 1 2 3 4 5 6
N = 51
N = 60
N = 22
N = 10
N = 85
N = 441
1 Cotter PE, et al. Neurology. 2013;80:
2 Etgen T, et al. Stroke. 2013;44:
3 Ritter MA, et al. Stroke. 2013;44:
4 Rojo-Martinez E, et al. Rev Neurol. 2013;57:
5 Christensen LM, et al. Eur J Neurol. 2014;21:
6 Sanna T, et al. N Engl J Med. 2014;370:

22. Summary: AF Detection Yield in Clinical
Studies of ICMs
AF Detection Yield (%)
NOTES
Average AF yields ranged from 16.1% to 33.7% in clinical studies of ICMs in the cryptogenic stroke setting.1-6
REFERENCES
Cotter PE, Martin PJ, Ring L, Warburton EA, Belham M, Pugh PJ. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology. 2013;80:
Etgen T, Hochreiter M, Mundel M, Freudenberger T. Insertable cardiac event recorder in detection of atrial fibrillation after cryptogenic stroke: an audit report. Stroke. 2013;44:
Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke. 2013;44:
Rojo-Martinez E, Sandin-Fuentes M, Calleja-Sanz AI, et al. [High performance of an implantable Holter monitor in the detection of concealed paroxysmal atrial fibrillation in patients with cryptogenic stroke and a suspected embolic mechanism]. Rev Neurol. 2013;57:
Christensen LM, Krieger DW, Hojberg S, et al. Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE study. Eur J Neurol. 2014;21:
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370: 1 2 3 4 5 6
N = 51
N = 60
N = 22
N = 10
N = 85
N = 441
1 Cotter PE, et al. Neurology. 2013;80:
2 Etgen T, et al. Stroke. 2013;44:
3 Ritter MA, et al. Stroke. 2013;44:
4 Rojo-Martinez E, et al. Rev Neurol. 2013;57:
5 Christensen LM, et al. Eur J Neurol. 2014;21:
6 Sanna T, et al. N Engl J Med. 2014;370:

23. Why Extended Monitoring?
Short- and intermediate-term monitoring may miss many patients with paroxysmal AF
79% of first AF episodes were asymptomatic at 12 months1
NOTES
It is clear that short-term and external monitoring, while convenient, has substantial limitations for the detection of AF inherent in the relatively limited durations these devices may be used.
In the CRYSTAL AF study, for example, the median time to detection of AF following cryptogenic stroke was 84 days—well outside the usual timeframe of external monitors. About 79% of first AF episodes were asymptomatic at 12 months.
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Note: For illustrative purposes only.
1 Sanna T, et al. N Engl J Med. 2014;370:

24. What is
Reveal LINQTM?
Provides up to 3 years of continuous cardiac monitoring
Smallest available insertable cardiac monitor
Simple, minimally invasive insertion procedure
Safe for use in MRI setting same day at 1.5 and 3.0 Tesla
20%
NOTES
The Medtronic Reveal LINQ ICM is a programmable device that continuously monitors a patient’s ECG and other physiological parameters for up to 3 years
It is the smallest available insertable cardiac monitor
It is inserted using a simple, minimally invasive procedure
Reveal LINQ ICM is safe for use in the MRI setting on the same day as insertion at 1.5 and 3.0 Tesla.
REFERENCE
Medtronic Inc. REVEAL LINQ LNQ11 Insertable Cardiac Monitor. Clinician Manual
Source: Medtronic, Inc. Reveal LINQ LNQ11 Insertable Cardiac Monitor. Clinician Manual

25. A Revolutionary System
The Complete Monitoring Solution
Improved CareLink™ User Interface
Wireless
20%
Reveal LINQ™ ICM
MyCareLink™ Patient Monitor
Cellular
NOTES
The Reveal LINQ monitor is part of a system that, together, provides a comprehensive long-term monitoring solution
The Reveal LINQ ICM is a small, leadless device that is inserted under the skin, in the chest. The device uses 2 electrodes on the body of the device to monitor the patient’s subcutaneous ECG continuously. The device memory can store up to 27 min of ECG recordings from automatically detected arrhythmias and up to 30 min of ECG recordings from patient-activated episodes
The Patient Assistant is a hand-held, battery-operated telemetry device that enables the patient to activate the recording of cardiac information in the Reveal LINQ ICM while experiencing or immediately after a symptomatic event. The clinician uses the recorded information to determine if the symptoms were associated with a cardiac event
Patients use the MyCareLink Patient Monitor to gather information automatically from their inserted device and communicate the information to their physician. The device communicates wirelessly with this monitor, which then transmits the information over a cellular telephone connection to the Medtronic CareLink Network. This daily wireless audit transmission is scheduled by the clinic and is usually set for a time when the patient is asleep. At other times, if requested to do so by their physician or clinic, the patient can use their monitor to perform a manual device interrogation to gather information from their inserted device and communicate it to their physician.
The Reveal system also includes a dedicated programmer. The programmer is used to set up the device to detect arrhythmias. It also allows the user to view, save, or print the information stored by the device.
REFERENCE
Medtronic Inc. REVEAL LINQ LNQ11 Insertable Cardiac Monitor. Clinician Manual
Simplified Insertion Procedure
Mobile Alerts
Patient Assistant
Streamlined Reports
All patient and clinical data are fictitious and for demonstration purposes only

26. 20% Reveal LINQ™ INSERTION NOTES
The device is programmed prior to insertion using the Medtronic CareLink programmer using Reveal LINQ FullView software.
The device is recommended to be positioned 45 degrees relative to the sternum over the 4th intercostal space, with the superior end of the device positioned approximately 2 cm left lateral from the sternal border.
The device may also be positioned over the 4th intercostal space approximately 2 cm parallel to the sternal border.
Incision is accomplished by means of a supplied incision tool and insertion by means of a dedicated insertion tool
REFERENCE
Medtronic Inc. REVEAL LINQ LNQ11 Insertable Cardiac Monitor. Clinician Manual
Source: Medtronic, Inc.

27. Reveal LINQ™ ICM System
The Reveal LINQ ICM continuously records heart rhythm data and sends them wirelessly to the MyCareLinkTM Patient Monitor
The MyCareLink Patient Monitor transmits data from the Reveal LINQ ICM to the clinic via a global cellular connection
The clinic receives easy-to-use and clinically actionable Reveal LINQ reports via the CareLinkTM Network
NOTES
This slide summarizes how the system works.
Source: Medtronic, Inc. Reveal LINQ LNQ11 Insertable Cardiac Monitor. Clinician Manual

28. Where Does Reveal LINQ™ Fit in the Pathway for ISCHEMIC STROKE?
Lacunar infraction: small vessel disease
Embolic appearing stroke with no history of AF:
Multiple foci of infarction
Cortical watershed distribution
Cerebellar
History of AF?
Standard stroke work-up
Standard stroke work-up
Antiplatelet agent
Standard stroke work-up
Anticoagulation
MRA or CTA of intracranial vessels
Transesophageal Echocardiogram (TEE)
Symptomatic carotid stenosis greater than 50%
Intracranial stenosis
Positive TEE
All testing negative?
CEA or stent
Anticoagulant
NOTES
This slide shows one potential algorithm in which Reveal LINQ is incorporated for appropriate patients. Please note that this pathway, which was provided by Dr Matthew C. Holtzman, represents the pattern in his practice. Medical judgment should be used to determine if this pathway is appropriate at individual centers.
Note that a standard stroke workup, in this case, was defined as:
Carotid Doppler
Telemetry bed
Fasting lipid panel
Glucose control
Blood pressure management
Hypercoagulation labs if the patient is aged <50 years
REFERENCE
Used with permission from Matthew C. Holtzman, MD. Neurology Michigan P.C.
This pathway represents Dr. Holtzman’s clinical practice. Medical judgment should be used to determine if adopting pathway is appropriate
No medical contraindications to insertion
Monofocal
Multifocal
Medical management
Antiplatelet agents
Angiogram
Lumbar puncture
Vasculitis work-up
Refer patient for Reveal LINQ insertion
Used with permission from Matthew C. Holtzman, MD. Neurology Michigan P.C.
This pathway represents Dr. Holtzman’s clinical practice. Medical judgment should be used to determine if adopting pathway is appropriate.

29. Conclusions
Approximately one-third of ischemic strokes are classified as cryptogenic, and many have previously undiscovered AF
The more you look, the more you find
Short- to intermediate-term cardiac rhythm monitoring may not be enough to detect paroxysmal AF in your cryptogenic stroke patients
CRYSTAL AF demonstrates superiority of continuous, long-term monitoring of cryptogenic stroke patients with an ICM
Reveal LINQ™ ICM
Up to 3 years of continuous cardiac monitoring with the world’s smallest ICM
Proven AF detection algorithm
Safe for use in MRI setting same day at 1.5 and 3.0 Tesla*
NOTES
This slide summarizes the complete presentation.
*Reveal LINQ ICM has been demonstrated to pose no known hazards in a specified MRI environment with specified conditions of use. Please see the Reveal LINQ ICM clinician manual or
MRI technical manual for more details.

30. Conclusions (continued)
CLINICAL IMPACT: More Appropriate Care
Reveal™ ICM detected over 7 times more patients with AF compared to standard monitoring at the 12-month end point
At 12 months, 97% of patients in the ICM arm who had AF detected were prescribed OAC
Reveal LINQ™ ICM should be included in hospital ICM protocols
20%

31. CRYPTOGENIC STROKE Patient Case Study
Reveal LINQTM
Insertable Cardiac Monitoring System
Reveal LINQTM
Insertable Cardiac Monitoring System

32. 20% Case study 51-year-old woman
Episode of unsteady gait and dizziness (< 1 hour)
On admission:
BP 140/86
HR 68 BPM
No neurologic deficits
After urgent MRI, admitted to intensive care unit for further assessment
20%
NOTES
A 51-year-old woman with a medical history of borderline hypertension experienced an episode of unsteady gait and dizziness that lasted <1 hour. On admission, her blood pressure was 140/86, her pulse was regular at 68 BPM and there were no neurologic deficits. After an urgent MRI, she was admitted to the intensive care unit for further assessment.

33. Case study
20%
NOTES
Results of an in-hospital ECG are shown below.

34. Case study
Two areas of infarct were identified in the left cerebellum
MRA of head and neck and chest x-ray returned normal results
TTE showed normal LV size and function
Subsequent TEE confirmed these results, also showed that her atrial size was at the upper limits of normal
TEE showed that there was no thrombus and normal velocities in the LAA, a normal aortic arch, and no evidence of a patent foramen ovale
24-hour telemetry monitoring was negative for arrhythmia
20%
NOTES
Two areas of infarct were identified in the left cerebellum.
An MRA of the head and neck, as well as a chest X ray, returned normal results.
Similarly, a TTE showed normal LV size and function.
A subsequent TEE confirmed these results, and also showed that her atrial size was at the upper limits of normal.
Further, the TEE showed that there was no thrombus and normal velocities in the LAA, a normal aortic arch, and no evidence of a patent foramen ovale.
24-hour telemetry monitoring was negative for arrhythmia.

35. Case study
Patient discharged on clopidogrel 75 mg/day and was followed for an additional 14 days with MCT
No arrhythmias identified during this period
NOTES
The patient was discharged on clopidogrel 75 mg/day and was followed for an additional 14 days with MCT
No arrhythmias were identified during this period

36. Case study
Five weeks after her initial stroke presentation, she developed a recurrence of unsteadiness and dizziness
Patient also developed a right-sided headache with nausea and vomiting
Symptoms lasted 2 hours
Patient was admitted to the ICU after an urgent brain MRI
NOTES
Five weeks after her initial stroke presentation, she developed a recurrence of unsteadiness and dizziness
She also developed a right-sided headache with nausea and vomiting
These symptoms lasted 2 hours
The patient was admitted to the ICU after an urgent brain MRI

37. Case study
NOTES
The second MRI revealed a new 3- to 4-cm right corpus striatum infarct with internal hemorrhage
There was a mild mass effect on the front horn of the right lateral ventricle

38. Case Study
SUMMARY
The patient underwent extensive additional evaluation, including a work-up for hypercoagulability, which was negative
She was subsequently implanted with an ICM and discharged on clopidogrel and aspirin
After 2 months of monitoring, episodes of paroxysmal AF lasting 15 to 90 minutes were detected
Episodes were asymptomatic despite mean ventricular rates in > 120 BPM
The patient was subsequently prescribed an oral anticoagulant
NOTES
The patient underwent extensive additional evaluation, including a work up for hypercoagulability, which was negative
She was subsequently implanted with an ICM and discharged on clopidogrel and aspirin
After 2 months of monitoring, episodes of paroxysmal AF lasting 15 to 90 minutes were detected. These episodes were asymptomatic despite mean ventricular rates in excess of 120 BPM
The patient was subsequently prescribed an oral anticoagulant

39. Primary End Point Results
CRYSTAL AF:
Primary End Point Results
NOTES
The primary end point of CRYSTAL AF was detection of AF at 6 months.
As shown in this figure, AF was detected at a rate of 8.9% of patients in the ICM group, as compared with 1.4% in the control group, yielding a hazard ratio of 6.4 (95% CI ; P<.001). <Sanna 2014, p 2482B>
ADDITIONAL INFORMATION
Although not reported in the study, the Number Needed to Screen at 6 months was 14.
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Source: Sanna T, et al. N Engl J Med. 2014;370:

40. Key Secondary End Point
CRYSTAL AF:
Key Secondary End Point
NOTES
A key secondary end point was detection of AF at 12 months.
At this time, AF was detected at a rate of 12.4% of patients in the ICM group, as compared with 2.0% in the control group (hazard ratio, 7.3; 95% CI ; P<.001). <Sanna 2014, p 2482A>
ADDITIONAL INFORMATION
Although not reported in the study, the Number Needed to Screen at 12 months was 10
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:
Source: Sanna T, et al. N Engl J Med. 2014;370:

41. Detection of AF at 36 Months
CRYSTAL AF:
Detection of AF at 36 Months
NOTES
Although not a primary or secondary end point, the CRYSTAL AF publication also includes information on the rate of AF detection at 36 months. <Sanna 2014, p 2483B>
At this time, AF was detected at a rate of 30% among patients in the ICM group, versus only 3 percent of the control group (HR 8.78; 95% CI 3.47, 22.19; P<.0001).
REFERENCE
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:

42. BRIEF STATEMENT
Reveal LINQ™ LNQ11 Insertable Cardiac Monitor and Patient Assistant
Indications
Reveal LINQ™ LNQ11 Insertable Cardiac Monitor
The Reveal LINQ Insertable Cardiac Monitor is an implantable patient-activated and automatically-activated monitoring system that records subcutaneous ECG and is indicated in the following cases:
patients with clinical syndromes or situations at increased risk of cardiac arrhythmias
patients who experience transient symptoms such as dizziness, palpitation, syncope and chest pain, that may suggest a cardiac arrhythmia.
This device has not been specifically tested for pediatric use.
Patient Assistant
The Patient Assistant is intended for unsupervised patient use away from a hospital or clinic. The Patient Assistant activates the data management feature in the Reveal Insertable Cardiac Monitor to initiate recording of cardiac event data in the implanted device memory.
Contraindications
There are no known contraindications for the implant of the Reveal LINQ Insertable Cardiac Monitor. However, the patient’s particular medical condition may dictate whether or not a subcutaneous, chronically implanted device can be tolerated.
Warnings/Precautions
Patients with the Reveal LINQ Insertable Cardiac Monitor should avoid sources of diathermy, high sources of radiation, electrosurgical cautery, external defibrillation, lithotripsy, therapeutic ultrasound and radiofrequency ablation to avoid electrical reset of the device, and/or inappropriate sensing as described in the Medical procedure and EMI precautions manual. MRI scans should be performed only in a specified MR environment under specified conditions as described in the Reveal LINQ MRI Technical Manual.
Operation of the Patient Assistant near sources of electromagnetic interference, such as cellular phones, computer monitors, etc., may adversely affect the performance of this device.
Potential Complications
Potential complications include, but are not limited to, device rejection phenomena (including local tissue reaction), device migration, infection, and erosion through the skin.
See the device manual for detailed information regarding the implant procedure, indications, contraindications, warnings, precautions, and potential complications/adverse events. For further information, please call Medtronic at 1 (800) and/or consult Medtronic’s website at
Caution: Federal law (USA) restricts this device to sale by or on the order of a physician.

43. BRIEF STATEMENT (Continued)
Medtronic MyCareLink™ Patient Monitor, Medtronic CareLink™ Network and CareLink™ Mobile Application
The Medtronic MyCareLink Patient Monitor and the Medtronic CareLink Network are indicated for use in the transfer of patient data from Medtronic implantable cardiac devices. These products are not a substitute for appropriate medical attention in the event of an emergency. Data availability and alert notifications are subject to Internet connectivity and access, and service availability. The MyCareLink Patient Monitor must be on and in range of the device. Alert notifications are not intended to be used as the sole basis for making decisions about patient medical care.
Intended Use The Medtronic MyCareLink™ Patient Monitor and CareLink™ Network are indicated for use in the transfer of patient data from some Medtronic implantable cardiac devices based on physician instructions and as described in the product manual. The CareLink™ Mobile Application is intended to provide current CareLink Network customers access to CareLink Network data via a mobile device for their convenience. The CareLink Mobile Application is not replacing the full workstation, but can be used to review patient data when a physician does not have access to a workstation. These products are not a substitute for appropriate medical attention in the event of an emergency and should only be used as directed by a physician. CareLink Network availability and mobile device accessibility may be unavailable at times due to maintenance or updates, or due to coverage being unavailable in your area. Mobile device access to the Internet is required and subject to coverage availability. Standard text message rates apply.
Contraindications
There are no known contraindications.
Warnings and Precautions The MyCareLink Patient Monitor must only be used for interrogating compatible Medtronic implantable devices.
See the device manual for detailed information regarding the implant procedure, indications, contraindications, warnings, precautions, and potential complications/adverse events. For further information, please call Medtronic at 1 (800) and/or consult Medtronic’s website at
Caution: Federal law (USA) restricts this device to sale by or on the order of a physician.
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Fax: (763)
Toll-free: 1 (800)
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